PROJECT SUMMARY/ABSTRACT This project will investigate the functions of electrical synapses within inhibitory circuits of the mammalian forebrain. Electrical synapses are gap junctions that interconnect neurons, and they serve as rapid, bidirectional communication pathways. A considerable amount is known about the basic biophysical properties of mammalian electrical synapses, their locations, and their dependence on the gap junction protein connexin36 (Cx36). Gap junctions can strongly influence the timing, phase, synchrony, probability, and rate of action potentials in pairs and small groups of neurons, yet we still do not know how electrical synapses contribute to larger network functions. The complexity of forebrain circuits has long been an impediment, but powerful new genetic and optical tools can now be brought to bear on these issues. Remarkably, in the mature thalamus and neocortex electrical synapses occur almost exclusively between GABAergic neurons. These junctions are quite specific; they usually interconnect inhibitory neurons of the same subtype in the cortex, and excitatory cells in the mature forebrain rarely express them. This investigation will focus on the roles of electrical synapses that interconnect inhibitory neurons of the thalamus (specifically in the somatosensory thalamic reticular nucleus, TRN), and several subtypes of interneurons in the neocortex (barrel cortex). There are three specific aims. The first is to determine the roles of electrical synapses in thalamocortical network activity, specifically slow (delta, theta) and fast (gamma) network oscillations studied in vitro and in vivo. We will use electrophysiology, selective deletion of Cx36 from subtypes of cortical and thalamic inhibitory cells, and optogenetics to control specific neurons and axonal pathways. The second aim is to test the hypothesis that electrical synapses play an important role in the powerful feedforward inhibitory circuits activated by both thalamocortical and corticothalamic pathways. The third aim is to define the spatial and cell type-specific organization of gap junction-coupled networks in somatosensory segments of the TRN and neocortex. Inhibitory circuits are universal, and essential for all sensory, motor, and cognitive functions; electrical synapses are ubiquitous components of inhibitory circuits. Abnormalities of inhibition are implicated in a wide variety of neurological, psychiatric, and developmental disorders, and mutations in gap junction genes are associated with epilepsy and other neurological dysfunctions. Our investigation will help to clarify the relevance and functions of electrical synapses in inhibitory systems of the forebrain.